Pearls from: Ronald Petersen, MD, PhD

Why the amyloid hypothesis is still alive

Questions have been raised about the amyloid hypothesis since several therapeutics aimed at the protein have failed. But Ronald Petersen, MD, PhD, of the Mayo Clinic, argues that the amyloid hypothesis isn't dead yet.

The following is a transcript of the discussion:

I think the amyloid hypothesis is still well, alive, and kicking. It's been challenged along the way because of some of the treatment failures aimed at amyloid itself. Nevertheless, I think there are certain reasons why those trials may have failed, and so the underlying hypothesis that amyloid may be the initiating event in a cascade of events that leads to maybe tau abnormalities, metabolic abnormalities, inflammation, and ultimately clinical changes down the road, I think that is still a viable hypothesis and certainly being investigated by many people. Now with some of our new imaging techniques, we can follow the deposition of amyloid, the deposition of tau in the brain over time and track clinical progression.

Now, we can see those same two entities, the plaques and the tangles, in the living individual using PET imaging. So now we can track people who are clinically normal, and as they progress on to cognitive impairment, we can see if the amyloid precedes the clinical impairment. We can see the amyloid develop. We can also use them, then, as targets of treatment and indices of whether the treatment is working.

So if we have an amyloid-based therapy, we image somebody at the outset of the trial, see if they have the plaques in the brain. We treat them for a year, year and a half, whatever it takes, and measure the amount of amyloid in the brain again at the end of the therapeutic trial with PET imaging and see if, in fact, we have been successful at removing the amyloid from the brain.

We can do the same thing with tau now. Tau is relatively new on the scene, but we can also measure tau presence at the beginning of a trial and tau presence at the end of a trial, and correlate it with any clinical changes, hopefully stabilization or maybe even improvement in cognitive function over the course of the trial.

Ultimately in the field of treatment of Alzheimer's disease, we're moving toward earlier and earlier identification of the disease process with the thought of intervening earlier rather than later. Ultimately, of course, we'd really like to prevent the disease. So what if we're able to image somebody who's clinically normal, find that they have, say, the amyloid protein in the brain, treat that, try to remove that protein from the brain to prevent them from becoming clinically impaired down the road? So, I think the underlying thought is that the earlier we intervene, the better we will be and perhaps we can even prevent the disease.

Amyloid is still the primary target of therapy currently being developed by most pharmaceutical companies, but there certainly are other targets. The other major feature of the disease, of course, is the neurofibrillary tangle comprised of tau. So, tau is actively being pursued as another therapeutic target. Antibodies against it. Anti-aggregation against it to see if, in fact, we can have an impact on that aspect of the disease.

In addition to amyloid and tau, of course, there are other features. There's inflammation. There are other neuropathologic deposits in the brain such as alpha-synuclein, TDP-43, and these may certainly cause clinical symptoms as well. So they're actively being pursued as possible targets for treatment. So while we focus on amyloid now, we're stretching it to tau. There certainly are other aspects of the disease, oxidation, neuroinflammation, that might be feasible targets as well.

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